The following discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgment or admission that any of the material referred to was published, known or part of the common general knowledge in any jurisdiction as at the priority date of the application.
Classical approaches in relieving acute pain therapy are presented, based on the search for ligands that interact with opioid receptors (OR) in the human body. There are three major groups of OR: mu (μ-), delta (δ-) and kappa (κ-) receptors. It is believed that those mainly responsible for the analgesic effect are mu-receptors, whereas delta and kappa have different physiological effects: analgesic, euphoric, dysphoric, respiratory depression, etc.
Often in patients with generalized stages of cancer there a combination of several types of pain observed, as are the sources of the pain. Therefore, pain is quite diverse in its clinical manifestations, but it has common characteristics—it is constant, and as a rule, it is also progressive in nature. In some patients, the pain is a result of tumor growth or its' spreading to other organs. In other cases, the pain can occur due to complications from cancer treatment. Approximately 3.5 million patients suffer from daily pain of varying intensity. According to statistics, about 40% of patients with intermediate stages of the disease, and 60-87% of the generalization of the disease experience pain ranging from mild to severe.
In cases of minor or medium manifestations of pain, both periodic and chronic in nature, drugs of the first and second order are used—non-narcotic drugs (non-opioid), non-steroidal anti-inflammatory drugs, or weak opioids (codeine, dionin, Tramal). Non-narcotic analgesics have no effect on the respiratory system, do not cause euphoria or physical and mental dependence. However, their analgesic activity manifests itself mainly with neuralgic, muscle, joint pain, headache, toothache. In cases of severe pain associated with injuries, surgery, malignant tumors and so on, they are commonly ineffective.
Another undesirable side effect of these drugs is the negative effect on the gastrointestinal tract, hematopoietic system and excretory system.
Over time, cancer patients, who have been receiving relatively weak drugs, find that they cease to have a pronounced effect. In such cases, use of opioid-based drugs is prescribed. The group of low-molecular narcotic analgesics (morphine and its derivatives) is characterized by a strong analgesic effect, which allows their use in case of injuries and diseases accompanied by severe pain (cancer, myocardial infarction, etc.). Despite this, this group has a big disadvantage—they have an effect on the central nervous system, which manifests itself in the development of euphoria, and when there is repeated use, of addictive syndromes are observed, as a result of psychic and physical dependence.
It is no secret that just this property allows someone to use them as street drugs and due to this problem, this drug group is under strict control from governments to avoid drug trafficking. Another negative factor is the relatively narrow therapeutic range of administered doses. The risk for adverse effects such as respiratory depression and loss of consciousness, can lead to severe consequences, including death.
The search for new analgesics is a highly topical problem of modern pharmacology as applied to the treatment of pain, primarily because painkillers do not have the necessary balance in efficiency and safety.
The search for peptide based analgesic drugs is an interesting and challenging problem in modern experimental pharmacology. In fact, the essence of natural endogenous peptides of this group of drugs is potentially highly effective and selective for the determination of analgesic and euphoric activities. Features of the chemical structure of several amino acids do not allow a peptide based drug to be chemically modified to induce euphoria.
There are several known studies where various substances have been tested for the presence of peptide based analgesic activity. Among endogenous analgesic peptides there are beta-endorphin, met-enkephalin, leu-enkephalin, dynorphin A. However, the drugs are not convenient to use, due to their biochemical characteristics and large molecules.
In the 1980's, a natural peptide was discovered, that has an affinity for the opioid receptor—dermorphin. Various forms and modifications of dermorphin-derived peptides have been studied.
A known heptapeptide having analgesic activity, combined with thermoregulatory and/or vasomotor activity and/or an impact on the behavioral response of a subject, and the way to change physiological activity of dermorphin [Patent RU No 2134121, was issued Aug. 10, 1999], and has the properties of endogenous analgesics. The use of this peptide provides a change in the level of analgesic activity and thermoregulatory source of dermorphin. However, the analgesic activity level of dermorphin that has been modified in this way, has shown that the activity level is not high enough.
At the same time, according to earlier studies dedicated to this issue, it was found that the minimum requirement for a complete sequence of dermorphin regarding its analgesic activity were represented by N-terminal tetrapeptide in which required the presence of D-Ala-residue [1].
Furthermore, it was shown that D-Arg2-dermorphin and N-terminal tetrapeptide analogs were resistant to cleavage and a peptide has a potent anti-nociceptive effect [2]. It was noted that the tetrapeptide H-Tyr-D-Ala-Phe-Gly-OH was the most resistant to cleavage.
Given the potential importance of this class of tetrapeptides for clinical applications, there were a number of applications filed for inventions JPS58213743 (A), published 12 Dec. 1983 and JPS6054400 (A), published 28 Mar. 1985.
Application JPS58213743 (A) pertaining to the possibility of obtaining tetrapeptides, in particular, H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-Sar-OH, indicated their potential activity associated with opioid receptors.
Application JPS6054400 indicated on the analgesic activity of tetrapeptides. In particular, given the presence of pronounced analgesic action of tetrapeptide Tyr-D-Arg-Phe-Gly-NH2 (more than 6 times the activity of morphine). This peptide was administered subcutaneously to mice in a condition of acute pain, wherein the solvent used was a ringer solution. In addition, the application describes the potential ability to prepare a composition for administration, without giving any examples of any such compositions.
A certain disadvantage of these tetrapeptides was the presence of some physical dependency and development of a tolerance to them [3]. During long-term administration of tetrapeptide Tyr-D-Arg-Phe-Gly-NH2 it led to the development of a tolerance in mice, to the analgesic effect of the peptide [4]. In another study, it was shown that rats also developed physical dependence, but the signs of addiction were significantly less pronounced than in the development of physical dependence to morphine [5]. This is due to a similar mechanism of action in tetrapeptides and small molecules in morphine-like substances, but significant difference in the manifestations of side effects tells about difference in the mechanism of action.
Most claimed tetrapeptide selectivity to different types of opioid receptors, as well as close to the natural metabolism of biochemical transformations internalized into the cell receptors provides milder effects of tolerance and dependence when used in therapeutic doses.
One of the most important features of the biological activities of the peptides H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-Sar-OH is the lack of serious side effects, such as effects on the central nervous system in the form of a disturbance of consciousness and the development of euphoria, as well as the lack of effect on the respiratory system.
Another positive feature of the noted tetrapeptides is the wide therapeutic range of application without significant side effects. These features allow the use of drugs based on tetrapeptides in a wider therapeutic range, outside of hospitals, in the field, or at home, which can be administered by low skilled personnel or by the patients' themselves.